•Pharmacologic therapy of D M

Management no

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• is associated with more stringent guidelines for the

treatment of comorbidities such as dyslipidemia and hypertension, it seems likely that the diagnostic criteria for diabetes will be lowered again to make

the fasting glucose cut points more sensitive.

•

Macrovascular disease & majority of the morbidity and mortality of DM

Medical Care for Patients with D M

Glycemic control

• It is clear that glucose levels above normal but below the current thresholds for diabetes (prediabetes) are associated with increased cardiovascular risk.

•Metformin • is representative of this class of agents.

• It reduces :• hepatic glucose production through an

undefined mechanism and• improves peripheral glucose utilization

slightly.

Biguanides

• reduces fasting plasma glucose • reduces insulin levels, • improves the lipid profile,• promotes modest weight loss

Metformin

Metformin

•The initial starting dose of 500 mg once or twice a day can be increased to 1000 mg bid.

Metformin• may have fewer gastrointestinal side effects :

• diarrhea, • anorexia,• nausea,• metallic taste

Metformin

•should be discontinued in patients who are: • seriously ill, • can take nothing orally, • receiving radiographic contrast

material

• should not be used in patients with: • renal insufficiency [serum creatinine > 1.5

mg/dL in men or > 1.4 mg/dL in women, • any form of acidosis,• CHF,• liver disease,

• severe hypoxia.

Metformin

Insulin Secretagogues

stimulate insulin secretion by interacting with the ATP-sensitive potassium channel on the beta cell .

Insulin Secretagogues

• are most effective in individuals with type 2 DM of relatively recent onset (<5 years).

• reduce both fasting and postprandial glucose and should be initiated at low doses and increased at 1- to 2-week intervals based on SMBG.

Sulfonylureas

• Most sulfonylureas are metabolized in the liver to compounds (some of which are active) that are cleared by the kidney.

• Thus, their use in individuals with significant hepatic or renal dysfunction is not advisable.

• Weight gain, a common side effect of sulfonylurea therapy, results from the increased insulin levels and improvement in glycemic control.

Sulfonylureas

Properties of Insulin Secretagogues

Sulfonylureas

• Gliclazide 80 mg 40 to 320 mg daily in two divided doses,

• - 30 mg and 60 mg modified release formulation

• may be given at a dose of 30 to 120 mg once daily at breakfast.

Sulfonylureas

• Glyburide (Glibenclamide) 5mg

• Doses of 1.25, 2.5, and 5 mg, • This drug is a major cause of drug induced hypoglycemia. • The risk is increased against other sulfonylureas.• Cholestatic jaundice is noted.• Glibenclamide may be contraindicated in those with G6PD deficiency, as it

may cause acute haemolysis.• Recently published data suggest glibenclamide is associated with

significantly higher annual mortality when combined with metformin than other insulin-secreting medications, after correcting for other potentially confounding patient characteristics.

• The safety of this combination has been questioned

Sulfonylureas

• Glimepiride(Amaryl) 1, 2 ,4 mg

• Side effects from taking glimepiride include gastrointestinal tract (GI) disturbances, occasional allergic reactions, and rarely blood production disorders including thrombocytopenia, leukopenia, and hemolytic anemia. In the initial weeks of treatment, the risk of hypoglycemia may be increased. Alcohol consumption and exposure to sunlight should be restricted because they can worsen side effects

Thiazolidinedionespromote a redistribution of fat from central to peripheral

locations. Circulating insulin levels decrease with use of the

thiazolidinediones, indicating a reduction in insulin resistance.

pioglitazone is 15–45 mg/d in a single daily dose, and for rosiglitazone the total daily dose is 2–8 mg/d administered either once daily or twice daily in divided doses.

• The FDA has issued an alert that: • rare patients taking these agents may

experience a worsening of diabetic macular edema.

• An increased risk of fractures has been noted in women taking these agents.

Thiazolidinediones

• Acarbose • Miglitol

• reduce postprandial hyperglycemia by delaying glucose absorption; they do not affect glucose utilization or insulin secretion

alfa -Glucosidase Inhibitors

Increatins memetic drugs

Increatins memetic drugs

• Liraglutide

• is a once-daily GLP-1 derivative for the treatment of type 2 diabetes.

• It reduces meal-related hyperglycemia (for 24 hours after administration) stimulate insulin secretion

• it shows negligible risk of hypoglycemia.

• It has the potential for inhibiting apoptosis

• stimulating regeneration of beta cells .• It decreases appetite and maintains body weight,

• It lowers blood triglyceride levels.

nce-weekly exenatide

• okayed by FDA for type 2 diabetes• lowered hemoglobin A1c by 1.6 percentage

points from baseline.• The most common adverse effects that emerged

in clinical trials were nausea (which usually decreased over time), hypoglycemia, vomiting, diarrhea, feeling jittery, dizziness, headache, dyspepsia, constipation, and asthenia.

Sitagliptin

• Tab Januvia® 25 50 100 mg• dipeptidyl peptidase-4 (DPP-4) inhibitor class.

• oral antidiabetic drug• less hypoglycemia, • less weight gain• often recommended to be combined with

other agents such as metformin

Insulin Preparations

• Banting and Best

First Human Patient

On Jan. 11, 1922, 14-year-old Leonard Thompson was the first human patient to receive insulin made by Banting and Best.

NPH insulin

• - Neutral Protamine Hagedorn• - insulin treated with protamine and zinc

protamine is a basic protein that readily complexes with insulin

zinc to yield particles that slowly dissolve in body fluids• onset of 1-2 hrs, peak of 6-12 hrs, duration of 18-

24 hrs

Insulin Preparations

NPH insulin

Regular insulin

Protaminezinc insulin

Hours

BloodGlucose

Lente Insulins

• suspensions of insulin in acetate buffer at neutral pH• - physical state and crystal size influences the rate of• absorption from the site of injection

Semilente insulin

Lenteinsulin

Ultralente insulin

Hours

BloodGlucose

•Rapidly acting analogue:Aspart (NovoRapid) Lispro(Humalog)Glulisine(Apidra)

• Long-acting insulin analogue :

Glargine(lantus)Detemir(Levemir)

analogues

• Short acting (regular) insulin is given30–45 min prior to a meal.

• Rapid acting insulin analoguesshould be injected just before (<20 min) or just after a meal.

Short acting &Rapid acting insulin

• available as a rapidly acting alternative to Regular insulin and • as an Biphasic insulins (rapidly acting+

intermediate-acting complex with protamine).

Aspart& Lispro

oproviding for both immediate and prolonged action. ocombination insulin formulations do not

allow independent adjustment of short-acting and long-acting activity. oSeveral insulin formulations are available

as insulin "pens," which may be more convenient for some patients.

Biphasic insulins (mixed insulins)

Insulin glargine( Lantus)

• given once daily • It consists of microcrystals that slowly release insulin, giving a long

duration of action of 18 to 26 hours,

• peakless• Pharmacokinetically, it resembles basal insulin secretion of non-

diabetic pancreatic beta cells. • Sometimes, in type 2 diabetes and in combination with a short acting

sulfonylurea (drugs which stimulate the pancreas to make more insulin), it can offer moderate control of serum glucose levels.

• In type 1 diabetes, depleted type 2 (in some cases) insulin glargine needs the support of fast acting insulin taken with food to reduce the effect of prandially derived glucose.

Multiple injection regimens,

• 1)Combination of Rapid-Acting Insulin Given with

Meals and Long-Acting Insulin at Bedtime (Basal plus approach )

• 2)Combination of Rapid-Acting and Intermediate-Acting Insulin with Breakfast and Dinner Intermediate-Acting

Insulin at Bedtime. (basal-bolus approach )

a continuous subcutaneous infusion of insulin (CSII) via an insulin pump

Insulin regimens

Basal plus approach

• Addition of basal insulin (glargine, detemir, or NPH/neutral protamine lispro

insulin) to previous treatment is accepted as the simplest way to start insulin therapy in those patients. But even when basal

insulin is adequately titrated, some patients will also need prandial insulin to achieve or maintain individual glycemic targets over time.

• In reducing hyperglycemia, this modality still remains the most effective option, even in people with type 2 diabetes..

• Diabetes Technol Ther. 2011 Jun;13 Suppl 1:S75-83. doi: 10.1089/dia.2011.0001

Basal-bolus approach

• Starting with premixed insulin is an effective option, but it is frequently

associated with increased hypoglycemia risk, fixed meal schedules, and weight gain.

• Diabetes Technol Ther. 2011 Jun;13 Suppl 1:S75-83. doi: 10.1089/dia.2011.0001

Open-loop systems comprise an infusion pump with the infusion rate programmed or controlled manually according to manual blood-glucose monitoring.

Closed-loop systems (the 'artificial pancreas') consist of an insulin pump, a glucose sensor, and a computer for analysis of blood-glucose data.

Continuous subcutaneous insulin infusion) (CSII)(external pump )

Preparations of Insulin• should not be subjected to storage conditions that

lead to freezing.• preparations in a refrigerator at 2 degrees to 8

degrees.• protected from excessive heat ,light, and sunlight.• most insulin preparations consider that storage by

the patient at a temperature of up to 25 degrees would be acceptable for up to one month.

Stability and storage

Glycemic management of type 2 diabetes

Strategy• 1)Reduce hypoglycemia• 2)minimize weight gain• 3)Minimal Insulin Resistance• 4)Minimal Effort• 5)Postprandial Targeting Strateg

• The AGIs and glitazones have been reported in small studies to reduce reactive hypoglycemia.

Theoretically, exenatide and

metformin should not be associated with hypoglycemia.

1)Reduce hypoglycemia.

• Diet and exercise and would almost certainly employ metformin as initial therapy. • Exenatide is associated with substantial

weight loss in most patients with long-term use .

2) strategy to minimize weight gain would emphasize

• The possible atherogenic effects of insulin have been widely touted in the lay press and by marketing programs within the pharmaceutical industry.

The relationship between circulating insulin levels and cardiovascular risk in nondiabetic populations is incontrovertible but probably

related to the presence of insulin resistance rather than the insulin concentrations per se.

3)Minimal Insulin Resistance Strategy

• There are no clinical data to suggest that exogenous insulin is associated with adverse side effects or long-term complications

• beyond its hypoglycemic effects and the

associated weight gain

3)Minimal Insulin Resistance Strategy

• The thiazolidinediones have the greatest efficacy in reducing insulin resistance,

• metformin is second,

• and AGIs are third.

• Exenatide has been demonstrated in animal models to produce modest improvement in insulin sensitivity and would be assumed to

reduce insulin resistance in parallel with weight;

• however, exenatide does increase postprandial insulin levels. • Nateglinide is associated with more specific stimulation of

insulin levels after meals than the other insulin secretagogues, which all increase peripheral insulin levels less than injected insulin.

3)Minimal Insulin Resistance Strategy

• Taking a once-a-day

• sulfonylurea or thiazolidinedione requires the least effort by the patient.

• At least one combination tablet taking advantage of this concept is available:

• rosiglitazone 4 mg in combination with

either 1 or 2 mg of glimepiride.

4)Minimal Effort Strategy

4)Minimal Effort Strategy

• Taking bedtime insulin is

actually relatively well accepted by patients to whom this consideration is important.

• Developing strategies to improve adherence and increase motivation is certainly a long-term goal in this population

• On the basis of epidemiologic studies, it has been suggested that :

• PPG is more highly correlated with cardiovascular disease risk than fasting glucose levels.• Furthermore, there are no outcome studies

that have demonstrated the superiority of these approaches in patients with T2DM

5)Postprandial Targeting Strategy

• Nonpharmacologic techniques that can improve postprandial control include :• lowering the carbohydrate content of

meals, • adding fiber,

• substituting monounsaturated fats for carbohydrates,

• and encouraging physical activity after meals

5)Postprandial Targeting Strategy

• The pharmacologic approach includes :• AGIs,• exenatide, Liraglutide• rapid-acting insulin analogues. • Nateglinide and repaglinide

5)Postprandial Targeting Strategy